Circumsporozoite Surface Protein-based malaria vaccines: a review

Abstract

Malaria represents a serious public health problem, presenting with high rates of incidence, morbidity and mortality in tropical and subtropical regions of the world. According to the World Health Organization, in 2018 there were 228 million cases and 405 thousand deaths caused by this disease in the world, affecting mainly children and pregnant women in Africa. Despite the programs carried out to control this disease, drug resistance and invertebrate vector resistance to insecticides have generated difficulties. An efficient vaccine against malaria would be a strategy with a high impact on the eradication and control of this disease. Researches aimed at developing vaccines have focused on antigens of high importance for the survival of the parasite such as the Circumsporozoite Surface Protein, involved in the pre-erythrocytic cycle during parasites invasion in hepatocytes. Currently, RTS'S is the most promising vaccine for malaria and was constructed using CSP; its performance was evaluated using two types of adjuvants: AS01 and AS02. The purpose of this review was to provide a bibliographic survey of historical researches that led to the development of RTS'S and its performance analysis over the decade. The search for new adjuvants to be associated with this antigen seems to be a way to obtain higher percentages of protection for a future malaria vaccine.

Figure 1. Schedule on the malaria vaccine development for approximately 50 years until 2019.

Figure 2. Structure of P. falciparum CSP. Approximately 420 amino acid residues. A: P. falciparum CSP is subdivided into three regions: CSP comprises an N-terminal region containing a signal peptide sequence and Region I; a Central region containing four-aminoacid (NANP) repeats and a B epitope; and a C-terminal region containing Region II [a thrombospondin (TSP)-like domain] and a canonical glycosylphosphatidylinositol (GPI) anchor additional sequence in addition to three T cell epitopes. The first epitope is CD4+ T cell (Th2R), which is located before the TSR, the second epitope is the CD8+ T cell (Th3R) within the TSR region and a “promiscuous” CD4 T cell epitope (CS.T3). B: The CSP region included in the RTS’S vaccine comprises the last 18 NANP repeats and C-terminus exclusive of the GPI anchor additional sequence. It contains 189 amino acids from CSP and 226 aa from Hepatitis B virus surface antigen (HBsAg) in RTS’S which are genetically fused to the truncated CSP and serve as protein carriers. The CSP fragment in RTS’S contains three known T-cell epitopes: a highly variable CD4+ T-cell epitope before the TSP-like domain (TH2R), a highly variable CD8+ T-cell epitope within the TSP-like domain (TH3R), and a conserved “universal” CD4 + T cell epitope (CS.T3) at the C-terminus.